Role of the stress kinase pathway in signaling via the T cell costimulatory receptor 4-1BB.
4-1BB is a member of the TNFR superfamily expressed on activated CD4+ and CD8+ T cells. 4-1BB can costimulate IL-2 production by resting primary T cells independently of CD28 ligation. In this study, we report signaling events following 4-1BB receptor aggregation using an Ak-restricted costimulation-dependent T cell hybridoma, C8.A3. Aggregation of 4-1BB on the surface of C8.A3 cells induces TNFR-associated factor 2 recruitment, which in turn recruits and activates apoptosis signal-regulating kinase-1, leading to downstream activation of c-Jun N-terminal/stress-activated protein kinases (JNK/SAPK). 4-1BB ligation also enhances anti-CD3-induced JNK/SAPK activation in primary T cells. Overexpression of a catalytically inactive form of apoptosis signal-regulating kinase-1 in C8.A3 T cells interferes with activation of the SAPK cascade and with IL-2 secretion, consistent with a critical role for JNK/SAPK activation in 4-1BB-dependent IL-2 production. Given the ability of both CD28 and 4-1BB to induce JNK/SAPK activation, we asked whether hyperosmotic shock, another inducer of this cascade, could function to provide a costimulatory signal to T cells. Osmotic shock of resting primary T cells in conjunction with anti-CD3 treatment was found to costimulate IL-2 production by the T cells, consistent with a pivotal role for JNK/SAPK in T cell costimulation.


Physical Activity in Adolescents Living in Rural and Urban New Caledonia: The Role of Socioenvironmental Factors and the Association With Weight Status.
Physical activity (PA) is an important factor for the prevention of overweight and obesity, particularly during adolescence. This study focuses on the understudied adolescent population of New Caledonia with the aim to (1) determine the daily PA levels and estimate the sedentary time through out-of-school sitting time; (2) highlight the influence of sociodemographic and environmental factors, and (3) assess the associations of PA and sitting time with overweight and obesity. A sample of 508 school-going adolescents living in New Caledonia was surveyed about their PA habits using the International Physical Activity Questionnaire-Short Form, as well as about the context in which they usually engage in PA. The influences of the place of living and ethnic community were also investigated. Results indicated that about 66% of the adolescents performed an average of at least 60 min of PA daily. Both Melanesian adolescent boys and girls were more active than Caucasian adolescents but only when they lived in rural areas (females: 115 vs. 93 min/day, p = 0.018; males: 133 vs. 97 min/day, p = 0.018). Indeed, PA was reduced in an urban environment (females: 88 min/day; males: 95 min/day, p = 0.028; rural vs. urban in Melanesian adolescents). Melanesian adolescents also spent less time in out-of-school sitting than Caucasian adolescents independently of where they lived (females: 164 vs. 295 min/day, p < 0.001; males: 167 vs. 239 min/day, p = 0.001). Feeling safe was positively associated with PA levels (females: ORadj = 2.85, p < 0.001; males: ORadj = 4.45, p < 0.001). In the adolescent boys, accessibility to a suitable place was also an important factor (ORadj = 2.94, p = 0.002). Finally, while PA and sitting time were negatively associated with overweight in male adolescents (ORadj = 0.28, p = 0.044 and ORadj = 0.39, p = 0.004), they were not in females. Living in a rural area allowed the Melanesian adolescents to maintain a more active lifestyle with more physical activities and less sitting time. Our results also indicated that safety was an important driver for engagement in PA. The urban environment in New Caledonia appears to be a contributor of a less active lifestyle in adolescents.


Moving toward the elimination of cervical cancer: modelling the health and economic benefits of increasing uptake of human papillomavirus vaccines.
The human papillomavirus (hpv) is a common sexually transmitted infection and a primary cause of cervical cancer. The Government of Canada has set a target of reaching 90% hpv vaccine coverage among adolescents by 2025. Here, we examine hpv vaccine uptake in school-based immunization programs across Canada and explore how achieving the 90% target could affect the future incidence of cervical cancer, mortality, and health system expenditures in a cohort of Canadian women. Data for hpv vaccine uptake in the most recent reported school year available in each jurisdiction were provided in 2017 by jurisdictional school-based immunization programs and were used to estimate a national weighted average of 67%. The OncoSim microsimulation model (version 2.5) was used to compare 3 different levels of hpv vaccine uptake (0%, 67%, 90%) on health and economic outcomes for a hypothetical cohort of all 5- to 10-year-old girls in Canada in 2015. Vaccine uptake for girls in school-based programs varied from 55.0% to 92.0% in the jurisdictions reviewed. The OncoSim model projects that increasing uptake to 90% from 67% would result in a 23% reduction in cervical cancer incidence rates (to 3.1 cases from 4.0 cases per 100,000, averaged across the lifetime of the cohort) and a 23% decline in the average annual mortality rate (to 1.0 deaths from 1.3 deaths per 100,000). Finally, the model projects that the health system will incur a cost of $9 million (1% increase) during the lifetime of the cohort if uptake is increased to 90% from 67%. Costs are discounted (1.5%) and expressed in 2016 Canadian dollars. Costs reflect the payer perspective. Our model shows that increasing hpv vaccine uptake to 90% from current levels for girls in school-based immunization programs could result in substantial reductions in the future incidence and mortality rates for cervical cancer in Canada.


Attractor dynamics reflect decision confidence in macaque prefrontal cortex.
Decisions are made with different degrees of consistency, and this consistency can be linked to the confidence that the best choice has been made. Theoretical work suggests that attractor dynamics in networks can account for choice consistency, but how this is implemented in the brain remains unclear. Here, we provide evidence that the energy landscape around attractor basins in population neural activity in prefrontal cortex reflects choice consistency. We trained two rhesus monkeys to make accept/reject decisions based on pretrained visual cues that signaled reward offers with different magnitudes and delays-to-reward. Monkeys made consistent decisions for very good and very bad offers, but decisions were less consistent for intermediate offers. Analysis of neural data showed that the attractor basins around patterns of activity reflecting decisions had steeper landscapes for offers that led to consistent decisions. Therefore, we provide neural evidence that energy landscapes predict decision consistency, which reflects decision confidence.


How do public health practitioners in China perceive injury prevention? A survey.
To report public health practitioners' perceptions of injury prevention in Changsha, China. We undertook a cross-sectional study at Changsha, Hunan, China. An anonymous self-reported survey was conducted to ascertain the proportion of respondents who answered negatively to questions about the value of injury prevention. Over 20% of respondents answered 'unpreventable' or 'don't know' to whether injuries from natural environmental disaster, homicide/assault, poisoning, animal bite, cut/pierce, suffocation and electric current were preventable. More than 40% of respondents answered 'no' or 'don't know' to whether the prevention of injuries from homicide/assault, cut/pierce, fall, suicide/self-harm, drowning, road traffic crash and fire/burn belonged to the job of public health. Only 48% of respondents supported building a division/office within the Centers for Disease Control and Preventions at all levels. Many public health practitioners in Changsha had misperception about injury prevention. Education and training are needed to correct their misperception.


High-dose trimetrexate and minimal-dose leucovorin: a case for selective protection?
Our objective was to find the minimum dose of leucovorin (LV; 5-formyltetrahydrofolate) needed to potentially provide selective protection of normal tissue in patients with tumors resistant to methotrexate (MTX) by virtue of transport during prolonged therapy with high-dose trimetrexate (TMTX). Based upon the known daily requirement for folate, that tumors are often resistant to methotrexate via a transport-based mechanism, and that large doses of trimetrexate can be given with large doses of leucovorin for the treatment of patients with Pneumocystis carinii, a protocol was designed to find the minimum LV dose required to allow the administration of large doses of TMTX. Patients were treated in 28-day cycles consisting of 14 consecutive days of oral TMTX (45 mg/m2 every 12 h), followed by 14 days of rest. The dose of concurrent LV was started at 5 mg/m2 twice daily. Cohorts of patients received successive half doses of LV so long as three consecutive patients had less than or equal to grade 3 toxicity. Ten patients received 29 courses of therapy. The most common toxicities encountered were thrombocytopenia (38%), mucositis (14%), and neutropenia (10%). At a LV dose of 2.5 mg/m2, toxicities were consistently limited to less than or equal to grade 3 and only one episode of grade 4 hematological toxicity. Although there was marked interpatient variability, the minimally effective LV dose for selective protection seems to be 2.5 mg/m2. If tumors are resistant to methotrexate because of decreased transport of drug (and also folate), then the same pharmacological principle used to develop TMTX/LV for the treatment of P. carinii may be applied to treatment of some patients with cancer.


Respiratory Viral Infection Alters the Gut Microbiota by Inducing Inappetence.
Respiratory viral infections are extremely common, but their impacts on the composition and function of the gut microbiota are poorly understood. We previously observed a significant change in the gut microbiota after viral lung infection. Here, we show that weight loss during respiratory syncytial virus (RSV) or influenza virus infection was due to decreased food consumption, and that the fasting of mice altered gut microbiota composition independently of infection. While the acute phase tumor necrosis factor alpha (TNF-α) response drove early weight loss and inappetence during RSV infection, this was not sufficient to induce changes in the gut microbiota. However, the depletion of CD8+ cells increased food intake and prevented weight loss, resulting in a reversal of the gut microbiota changes normally observed during RSV infection. Viral infection also led to changes in the fecal gut metabolome, with a significant shift in lipid metabolism. Sphingolipids, polyunsaturated fatty acids (PUFAs), and the short-chain fatty acid (SCFA) valerate were all increased in abundance in the fecal metabolome following RSV infection. Whether this and the impact of infection-induced anorexia on the gut microbiota are part of a protective anti-inflammatory response during respiratory viral infections remains to be determined.IMPORTANCE The gut microbiota has an important role in health and disease: gut bacteria can generate metabolites that alter the function of immune cells systemically. Understanding the factors that can lead to changes in the gut microbiome may help to inform therapeutic interventions. This is the first study to systematically dissect the pathway of events from viral lung infection to changes in gut microbiota. We show that the cellular immune response to viral lung infection induces inappetence, which in turn alters the gut microbiome and metabolome. Strikingly, there was an increase in lipids that have been associated with the resolution of disease. This opens up new paths of investigation: first, what is the (presumably secreted) factor made by the T cells that can induce inappetence? Second, is inappetence an adaptation that accelerates recovery from infection, and if so, does the microbiome play a role in this?


European Society for Medical Oncology (ESMO) 2018 Congress Twitter analysis: from ethics to results through the understanding of communication and interaction flows.
Twitter is a microblogging service providing a platform for social networking. For medical information, Twitter is an interesting channel for sharing and spreading information and as an engagement platform for different stakeholders. Benefits and caveats of uncontrolled medical information must be carefully pondered, considering the possible intended and unintended adverse outcomes of uncontrolled influencing. The aim of this study was to describe the non-commercial content shared on Twitter and to analyse the level of influence of commercial tweeters during the European Society of Medical Oncology (ESMO) 2018 annual meeting held in Munich. A retrospective analysis of the tweets shared in the period 19-23 October 2018 indexed with the hashtag #ESMO18 or #ESMO2018 was performed; methodology of systematic reviews was mirrored. Commercial tweeters (pharmaceutical and biotechnology companies, device manufacturers and spam tweeters) were excluded from the primary analysis, and only non-commercial tweets from and about the congress were included. Tweets were analysed using a network analytical tool (NodeXL). A total of 7100 tweets posted by 1334 tweeters were identified for the period of interest. Less than 10% of tweeters were identified as commercial, posting 15.7% of tweets and receiving almost one-quarter of retweets. However, pharmaceutical and biotech tweeters were substantially less likely to be mentioned by other tweeters. All of the top 10 retweeters of non-commercial content were clinicians and/or professional organisations, in stark contrast with the commercial content. The use of social networks in medical meetings, including oncology, is increasing for real-time communication and informed opinion-making. The uncontrolled spread of information on Twitter can both stimulate discussions on non-official and non-canonical channels of communication and provide uncontrolled influencing of diverse stakeholders. The disclosure of financial declarations of interest on Twitter could enhance the transparency of the information, as is already happening in medical journals.


Intensity-modulated radiation therapy for patients with 1 to 3 brain metastases in recursive partitioning analysis class 3.
The prognosis is extremely poor for patients with brain metastases in recursive partitioning analysis (RPA) class 3. It is not clear whether dose elevation for brain lesions in addition to whole-brain radiotherapy could improve survival for those patients. This study aimed to assess the efficacy and safety of dose elevation with intensity-modulated radiation therapy (IMRT) for patients with 1 to 3 brain metastases in RPA class 3.From January 2013 to December 2015, 24 patients with 1 to 3 brain metastases in RPA class 3 were included in this study. The median age was 60 (range 41-85) years and the mean graded prognostic assessment (GPA) score was 1.25 (range 0.5-2). Whole-brain radiotherapy (30 Gy) with a simultaneous integrated boost (SIB) to the brain metastases (totaling 40 Gy) was delivered in 10 fractions using IMRT technique. Survival times and overall safety were assessed. The significance of prognostic variables on survival was assessed by both univariate and multivariate analyses.All of the patients completed the planned SIB schedule. The overall response rate was 66.7%. The median survival time (MST) was 8 months for the entire group of patients. The MST was 5 months for patients with a GPA score of 0.5 to 1 (n = 11 patients) and 12 months with a GPA score of 1.5 to 2 (n = 13 patients). No acute or late toxicities greater than grade 2 were detected. Age and subsequent chemotherapy were significantly associated with MST on univariate and multivariate analyses.It is feasible to elevate radiation doses to 40 Gy using the IMRT technique in RPA class 3 patients with 1 to 3 brain metastases without serious toxicities. The preliminary results are encouraging and further studies with larger cohorts are warranted.


Species specialization limits movement ability and shapes ecological networks: the case study of 2 forest mammals.
To counteract the negative effects of forest fragmentation on wildlife, it is crucial to maintain functional ecological networks. We identified the ecological networks for 2 mammals with very different degrees of forest specialization, the European badger Meles meles and the Roe deer Capreolus capreolus, by differentiating 4 agroforestry elements as either nodes or connectivity elements, and by defining the distance that provides the functional connectivity between fragments. Species occurrence data were collected in a wide agroecosystem in northern Italy. To test the role of hedgerows, traditional poplar cultivations, short rotation coppices, and reforestations as ecological network elements for the 2 species we applied the method of simulated species perceptions of the landscape (SSPL), comparing the ability of different SSPLs to explain the observed species distribution. All analyses were repeated considering different scenarios of species movement ability through the matrix. Model outputs seem to show that the specialist and highly mobile Roe deer has the same movement ability throughout the matrix (2 km) as the European badger, a smaller, but generalist species. The ecological network identified for the European badger was widespread throughout the area and was composed of woodlands, poplar cultivations and hedgerows as nodes and short rotation coppices as connectivity elements. Conversely, the ecological network of the Roe deer was mostly limited to the main forest areas and was composed of woodlands, poplar cultivations and reforestations as nodes and short rotation coppices and hedgerows as connectivity elements. The degree of forest specialization strongly affects both species perception of habitat and movement ability throughout the matrix, regardless of species size. This has important implications for species conservation.


Determination of albumin in bronchoalveolar lavage fluid by flow-injection fluorometry using chromazurol S.
A highly sensitive flow injection fluorometry for the determination of albumin was developed and applied to the determination of albumin in human bronchoalveolar lavage fluids (BALF). This method is based on binding of chromazurol S (CAS) to albumin. The calibration curve was linear in the range of 5-200 microg/ml of albumin. A highly linear correlation (r=0.986) was observed between the albumin level in BALF samples (n=25) determined by the proposed method and by a conventional fluorometric method using CAS (CAS manual method). The IgG interference was lower in the CAS flow injection method than in the CAS manual method. The albumin level in BALF collected from healthy volunteers (n=10) was 58.5+/-13.1 microg/ml. The albumin levels in BALF samples obtained from patients with sarcoidosis and idiopathic pulmonary fibrosis were increased. This finding shows that the determination of albumin levels in BALF samples is useful for investigating lung diseases and that CAS flow injection method is promising in the determination of trace albumin in BALF samples, because it is sensitive and precise.


Neuropathological evaluation of an 84-year-old man after 422 ECT treatments.
Concern remains among many that electroconvulsive therapy (ECT) causes "brain damage." This ambiguous term presumably refers to lesions that could, in principle, be observed either grossly or microscopically in postmortem studies, and the assertion that it occurs appears to be based largely on old reports with dubious relevance to modern practice. Fortunately, using modern technique, ECT is so safe that mortality around the time of treatment is extraordinarily rare and as a result there has been little opportunity for postmortem examination of individuals who had recently had ECT. We report a case in which postmortem brain examination was performed roughly a month after the patient's last treatment.


Dietary carbohydrate type and fat amount alter VLDL and LDL metabolism in guinea pigs.
The effects of low/high fat diets and simple/complex carbohydrate intake on specific aspects of plasma VLDL and LDL metabolism were evaluated. Guinea pigs were fed for 4 wk two different fat/carbohydrate concentrations: 2.5/58 (g/100 g) or 25/29 (g/100 g) with either sucrose or cornstarch as the sole carbohydrate source. Intake of high fat diets resulted in higher plasma cholesterol (P < 0.001), whereas sucrose intake resulted in higher plasma triacyglycerol (TAG) concentrations (P < 0.03). Intake of starch increased apolipoprotein (apo) B secretion rates (P < 0.001), and nascent VLDL were smaller and contained less TAG/apo B than particles from the sucrose-fed group (P < 0.01). Guinea pigs fed the starch diets had higher plasma VLDL apo B flux and faster VLDL apo B clearance than those fed sucrose diets (P < 0.01). In addition, more rapid VLDL removal from plasma in guinea pigs fed complex carbohydrate/high fat diets was associated with less conversion of VLDL to LDL and lower plasma cholesterol concentrations compared with the high fat/sucrose group (P < 0.01). Low fat compared with high fat intake resulted in 60% more rapid plasma LDL apo B fractional catabolic rates (FCR). The LDL apo B fractional catabolic rate of all dietary groups was inversely correlated with plasma cholesterol concentrations (r = -0.83, P < 0.001). These results demonstrate that in guinea pigs, low fat diets decrease plasma LDL cholesterol concentrations by increasing LDL turnover rates, and complex carbohydrates reduce plasma TAG by affecting the composition of nascent VLDL particles and by increasing VLDL apo B catabolism.


Loss of surface beta-2 adrenoceptors accounts for the insensitivity of cultured human monocytes to beta-2 adrenoceptor agonists.
The short-acting beta-2 adrenoceptor agonists (β(2)-agonists), such as salbutamol, are effective bronchodilators used to treat asthma. They lack significant anti-inflammatory effect in vivo as well as on isolated alveolar macrophages even though they exhibit this effect on freshly isolated monocytes. The purpose of this study was to determine if this observation is related to a change in the expression and/or function of surface β(2)-receptors during the differentiation of these cells to macrophages. Purified monocytes, cultured for 1-48 h were pre-treated with the β(2)-agonists (salbutamol or procaterol) or PGE(2) before being stimulated with bacterial lipopolysaccharide (LPS). Subsequently, the amount of TNF-α (a typical inflammatory mediator) released over 24 h, as well as agonist-stimulated cAMP, were determined by enzyme immunoassays. Western blotting techniques were used to study the expression of the membrane β(2)-receptor protein. Results showed that in freshly isolated human monocytes, both the β(2)-agonists and PGE(2) significantly inhibited LPS-induced TNF-α release as well as increased intracellular cAMP. After culturing adherent monocytes for 24-48 h, the ability of the β(2)-agonists to produce both effects was completely lost, whereas that of PGE(2) was essentially intact. Western blotting data showed a near complete loss of surface expression of β(2)-receptors in cells cultured for ≥24 h. These results show that as human monocytes adhere to surfaces to begin differentiation into macrophages, they selectively lose their surface β(2)-receptors and hence become insensitive to the anti-inflammatory effect of β(2)-agonists. This may explain why β(2)-agonists lack significant anti-inflammatory effect on alveolar macrophages or in clinical asthma.


High-Quality Few-Layer Graphene on Single-Crystalline SiC thin Film Grown on Affordable Wafer for Device Applications.
Graphene is promising for next-generation devices. However, one of the primary challenges in realizing these devices is the scalable growth of high-quality few-layer graphene (FLG) on device-type wafers; it is difficult to do so while balancing both quality and affordability. High-quality graphene is grown on expensive SiC bulk crystals, while graphene on SiC thin films grown on Si substrates (GOS) exhibits low quality but affordable cost. We propose a new method for the growth of high-quality FLG on a new template named "hybrid SiC". The hybrid SiC is produced by bonding a SiC bulk crystal with an affordable device-type wafer and subsequently peeling off the SiC bulk crystal to obtain a single-crystalline SiC thin film on the wafer. The quality of FLG on this hybrid SiC is comparable to that of FLG on SiC bulk crystals and much higher than of GOS. FLG on the hybrid SiC exhibited high carrier mobilities, comparable to those on SiC bulk crystals, as anticipated from the linear band dispersions. Transistors using FLG on the hybrid SiC showed the potential to operate in terahertz frequencies. The proposed method is suited for growing high-quality FLG on desired substrates with the aim of realizing graphene-based high-speed devices.


Individualizing the definition of seizure clusters based on temporal clustering analysis.
Seizure clusters are often encountered in people with poorly controlled epilepsy. Detection of seizure clusters is currently based on simple clinical rules, such as two seizures separated by four or fewer hours or multiple seizures in 24 h. Current definitions fail to distinguish between statistically significant clusters and those that may result from natural variation in the person's seizures. Ability to systematically define when a seizure cluster is significant for the individual carries major implications for treatment. However, there is no uniform consensus on how to define seizure clusters. This study proposes a principled statistical approach to defining seizure clusters that addresses these issues. A total of 533,968 clinical seizures from 1,748 people with epilepsy in the Seizure Tracker™ seizure diary database were used for algorithm development. We propose an algorithm for automated individualized seizure cluster identification combining cumulative sum change-point analysis with bootstrapping and aberration detection, which provides a new approach to personalized seizure cluster identification at user-specified levels of clinical significance. We develop a standalone user interface to make the proposed algorithm accessible for real-time seizure cluster identification (ClusterCalc™). Clinical impact of systematizing cluster identification is demonstrated by comparing empirically-defined clusters to those identified by routine seizure cluster definitions. We also demonstrate use of the Hurst exponent as a standardized measure of seizure clustering for comparison of seizure clustering burden within or across patients. Seizure clustering was present in 26.7 % (95 % CI, 24.5-28.7 %) of people with epilepsy. Empirical tables were provided for standardizing inter- and intra-patient comparisons of seizure cluster tendency. Using the proposed algorithm, we found that 37.7-59.4 % of seizures identified as clusters based on routine definitions had high probability of occurring by chance. Several clusters identified by the algorithm were missed by conventional definitions. The utility of the ClusterCalc algorithm for individualized seizure cluster detection is demonstrated. This study proposes a principled statistical approach to individualized seizure cluster identification and demonstrates potential for real-time clinical usage through ClusterCalc. Using this approach accounts for individual variations in baseline seizure frequency and evaluates statistical significance. This new definition has the potential to improve individualized epilepsy treatment by systematizing identification of unrecognized seizure clusters and preventing unnecessary intervention for random events previously considered clusters.


Cation-pi bonding and amino-aromatic interactions in the biomolecular recognition of substituted ammonium ligands.
Cation-pi bonds and amino-aromatic interactions are known to be important contributors to protein architecture and stability, and their role in ligand-protein interactions has also been reported. Many biologically active amines contain substituted ammonium moieties, and cation-pi bonding and amino-aromatic interactions often enable these molecules to associate with proteins. The role of organic cation-pi bonding and amino-aromatic interactions in the recognition of small-molecule amines and peptides by proteins is an important topic for those involved in structure-based drug design, and although the number of structures determined for proteins displaying these interactions is small, general features are beginning to emerge. This review explores the role of cation-pi bonding and amino-aromatic interactions in the biological molecular recognition of amine ligands. Perspectives on the design of ammonium-ligand-binding sites are also discussed.


Overactivation of fear systems to neutral faces in schizophrenia.
The amygdala plays a central role in detecting and responding to fear-related stimuli. A number of recent studies have reported decreased amygdala activation in schizophrenia to emotional stimuli (such as fearful faces) compared with matched neutral stimuli (such as neutral faces). We investigated whether the apparent decrease in amygdala activation in schizophrenia could actually derive from increased amygdala activation to the neutral comparator stimuli. Nineteen patients with schizophrenia and 24 matched control participants viewed pictures of faces with either fearful or neutral facial expressions, and a baseline condition, during functional magnetic resonance imaging scanning. Patients with schizophrenia showed a relative decrease in amygdala activation to fearful faces compared with neutral faces. However, this difference resulted from an increase in amygdala activation to the neutral faces in patients with schizophrenia, not from a decreased response to the fearful faces. Patients with schizophrenia show an increased response of the amygdala to neutral faces. This is sufficient to explain their apparent deficit in amygdala activation to fearful faces compared with neutral faces. The inappropriate activation of neural systems involved in fear to otherwise neutral stimuli may contribute to the development of psychotic symptoms in schizophrenia.


Anti-T antibodies and peanut-agglutinin-binding glycoproteins in sera of patients with gastric cancer.
Agglutinating antibodies to neuraminidase-treated red blood cells (anti-T agglutinins) are known to be reduced in patients with gastric cancer. The antigenic determinant of anti-T agglutinin is known to have a disaccharide structure [Gal(beta1-3)GalNAc], the same specificity as peanut agglutinin (PNA). We examined sera of 27 patients with gastric cancer and 30 controls for anti-T agglutinins, anti-T antibodies and PNA-binding glycoproteins. Anti-T agglutinins were titrated by a microtiter hemagglutination method. Levels of anti-T antibodies were determined by enzyme immunoassay using synthetic glycoconjugate [Gal(beta1-3)GalNAc O-alpha-linked to human serum albumin] as an antigen. Levels of PNA-binding glycoproteins in sera were measured by sandwich enzyme-linked lectin assay using wheat germ agglutinin and peroxidase-conjugated PNA. Titers of anti-T agglutinins were significantly lower in patients with gastric cancer than in controls (P = 0.041). Levels of anti-T antibodies were not significantly different in patients with gastric cancer and controls; however, decreased levels of anti-T antibodies were more frequent in patients with gastric cancer than in controls (P = 0. 001). Levels of PNA-binding glycoproteins were significantly higher in sera of patients with gastric cancer than in controls (P = 0.001). The levels of anti-T antibodies inversely correlated with the levels of PNA-binding glycoproteins in sera of patients with gastric cancer (r = -0.44, P = 0.021). These results suggest that the decrease in anti-T antibodies in sera of patients with gastric cancer might be due to immune complex formation between circulating PNA-binding glycoproteins and anti-T antibodies.


Copper efflux is induced during anaerobic amino acid limitation in Escherichia coli to protect iron-sulfur cluster enzymes and biogenesis.
Adaptation to changing environments is essential to bacterial physiology. Here we report a unique role of the copper homeostasis system in adapting Escherichia coli to its host-relevant environment of anaerobiosis coupled with amino acid limitation. We found that expression of the copper/silver efflux pump CusCFBA was significantly upregulated during anaerobic amino acid limitation in E. coli without the supplement of exogenous copper. Inductively coupled plasma mass spectrometry analysis of the total intracellular copper content combined with transcriptional assay of the P(cusC)-lacZ reporter in the presence of specific Cu(I) chelators indicated that anaerobic amino acid limitation led to the accumulation of free Cu(I) in the periplasmic space of E. coli, resulting in Cu(I) toxicity. Cells lacking cusCFBA and another copper transporter, copA, under this condition displayed growth defects and reduced ATP production during fumarate respiration. Ectopic expression of the Fe-S cluster enzyme fumarate reductase (Frd), or supplementation with amino acids whose biosynthesis involves Fe-S cluster enzymes, rescued the poor growth of ΔcusC cells. Yet, Cu(I) treatment did not impair the Frd activity in vitro. Further studies revealed that the alternative Fe-S cluster biogenesis system Suf was induced during the anaerobic amino acid limitation, and ΔcusC enhanced this upregulation, indicating the impairment of the Fe-S cluster assembly machinery and the increased Fe-S cluster demands under this condition. Taken together, we conclude that the copper efflux system CusCFBA is induced during anaerobic amino acid limitation to protect Fe-S cluster enzymes and biogenesis from the endogenously originated Cu(I) toxicity, thus facilitating the physiological adaptation of E. coli.


[Duodenal atresia in the newborn].
The specific features of intrauterine development and pheno- and genotypic characteristics were studied in newborn infants with duodenal atresia. Main anthropometric parameters at birth (weight, height, and head and chest circumferences), concomitant developmental malformations, gene frequencies and phenotypic combinations of ABO and Rhesus factor blood groups were analyzed. The babies with duodenal atresia were found to have considerably impaired intrauterine development, multiple concomitant hypoplastic developmental abnormalities, significantly higher frequencies of the ORh+ phenotype, and lower frequencies of the ARh+ phenotype.


Immunogenic Peptides from Pap31 and SCS-α of Bartonella bacilliformis: One Step Closer to a Rapid Diagnostic Tool for Carrion's Disease.
Bartonella bacilliformis is the causal agent of Carrion's disease, an overlooked illness endemic in the Andean Mountains with Peru being the most affected country. The diagnostic of this illness is a challenge due to the limited resources and the common symptomatology with other infectious diseases. The goal of this study was to identify immunogenic peptides from Pap31 and succinyl-CoA synthetase α (SCS-α) of B. bacilliformis that might be suitable for developing a serologic tool. The immunodominant character of Pap31 and SCS-α was determined by Western blotting and in-silico analysis. Subsequently, 35 peptides were selected for epitope mapping and their immunoreactivity was tested by enzyme-linked immunosorbent assay (ELISA). A total of 30 sera were tested including pre-exposed people with high IgM levels for Pap31/SCS-α (23 sera), patients (2 sera) as well as 5 sera with no reactivity to Pap31/SCS-α. The results indicate that Pap31-8 (187QAIGSAILKGTKDTGT202) and SCS-α-12 (59IFASVAEGKEKTGANA74) are the most immunogenic peptides, with Pap31-8 showing potential to discriminate between B. bacilliformis and the remaining Bartonella spp., and SCS-α-12 differentiating Bartonella spp. from other microorganisms.


Programming optimal atrioventricular delay in dual chamber pacing using peak endocardial acceleration: comparison with a standard echocardiographic procedure.
Optimization of programmed atrioventricular delay in dual chamber pacing is essential to the hemodynamic efficiency of the heart. Automatic AV delay optimization in an implanted pacemaker is highly desirable. Variations of peak endocardial acceleration (PEA) with AV delay at rest correlate well with echocardiography derived observations, particularly with end-diastolic filling and mitral valve closure timings. This suggests the possibility of devicing a procedure for the automatic determination of the optimal AV delay. The aim of this study was to compare a proposed algorithm for optimal AV delay determination with an accepted echocardiographic method. Fifteen patients with high degree AV block received BEST-Living pacing systems. Automatic AV delay scans were performed at rest (60-300 ms in 20-ms steps with 60 beats per step) in DDD at 90 ppm, while simultaneously recording cycle-by-cycle PEA values, which were averaged for each AV delay to obtain a PEA versus AV delay curve. Nonlinear regression analysis based on a Boltzmann sigmoid curve was performed, and the optimal AV delay (OAVD) was chosen as the sigmoid inflection point of the regression curve. The OAVD was also evaluated for each patient using the Ritter echocardiographic method. Good sigmoid fit was obtained in 13 of 15 patients. The mean OAVD obtained by the PEA sigmoid algorithm was 146.9 +/- 32.1 ms, and the corresponding result obtained by echocardiography was 156.4 +/- 34.3 ms (range 31.8-39.7 ms). Correlation analysis yielded r = 0.79, P = 0.0012. In conclusion, OAVD estimates obtained by PEA analysis during automatic AV delay scanning are consistent with those obtained by echocardiography. The proposed algorithm can be used for automatic OAVD determination in an implanted pacemaker pulse generator.


Transconjunctival versus Transcutaneous Injection of Botulinum Toxin into the Lacrimal Gland to Reduce Lacrimal Production: A Randomized Controlled Trial.
The purpose of this study was to determine and compare the effects between injecting botulinum toxin A (BTX-A) transconjunctivally into the palpebral lobe and transcutaneously into the orbital lobe of the lacrimal gland in patients with epiphora due to lacrimal outflow obstruction. This randomized controlled study included 53 eyes of 31 patients with unilateral or bilateral epiphora. Patients were randomly allocated to receive an injection of BTX-A (3 units) either transconjunctivally (n = 15, 25 eyes) or transcutaneously (n = 16, 28 eyes). For objective assessments, the tear meniscus height and Schirmer's I test with topical anesthesia were measured at baseline and after 2, 6, 12, and 24 weeks of follow-up. Subjective evaluations were performed using the Munk score. After BTX-A injection, patients in both groups experienced significant objective and subjective reductions in tearing at all follow-up times compared to pre-injection (success rate 86.8%), and the effect lasted for a mean duration of 5.63 months. The two delivery routes showed similar clinical effectiveness for a single injected dose of BTX-A. In conclusion, injecting BTX-A via either a transconjunctival or transcutaneous route helps to reduce normal tear production and results in significant improvements in the symptoms in patients with epiphora.


Association of KIR3DS1+HLA-B Bw4Ile80 combination with susceptibility to tuberculosis in Lur population of Iran.
Natural killer (NK) cells are the effector cells of innate immunity that respond to infection and tumor. Interactions between killer cell immunoglobulin like receptors (KIR) and human leukocyte antigen (HLA) class I molecules regulate NK cells responses to eliminate infected and transformed cells. To investigate the impact of KIR genes, HLA ligand genes, and KIR-HLA combinations on susceptibility to tuberculosis (TB) in Lur population of Iran. The genomic DNA of 50 patients with TB from Lorestan province of Iran was genotyped for sixteen KIR genes and their five major HLA class I ligands were determined by a polymerase chain reaction-sequence-specific primers (PCR-SSP) assay. The results were compared with those of 200 healthy unrelated Iranian individuals. In Lur population of Iran, a significant decrease in frequency of KIR3DS1 was found in TB patients compared to control group (24% vs. 44.5%, OR=0.394, CI=0.194-0.798, p=0.013). Also, among the three activating genes that may use HLA class I molecules as their ligands, a significant decrease was shown in frequency of KIR3DS1 with HLA-B Bw4Ile80 ligand in TB patients compared to control group (4% vs. 23%, OR=0.14, CI=0.033-0.596, p=0.004). These findings imply a genetic imbalance between activating and inhibitory KIR genes and KIR-HLA combinations in Lur TB patients. Low level of activating KIR3DS1 and its combination with HLA-B Bw4Ile80 ligand might have an influence on the susceptibility to TB in Lur population of Iran.


Combined nerve, vessel, and tendon injuries of the volar wrist: Multidisciplinary treatment and functional outcomes.
The superficial location of critical structures, including tendons, nerves and vessels, in the volar surface of the wrist makes them vulnerable to penetrating trauma. Extensive injuries to these structures are described as "spaghetti wrist". The main objective of this study was to report functional outcome in spaghetti-wrist injuries. The records of patients presenting to our clinic with extensive volar wrist injuries between January 2016 and January 2019 were reviewed retrospectively. Age, gender, comorbidities, date of injury, injury mechanism, affected hand and transected structures were noted. Tendon function, opposition, intrinsic hand function, deformity and sensitivity were evaluated following the Noaman report. The Michigan Hand Outcomes Questionnaire (MHOQ) was used to evaluate hand-specific outcomes. Twenty patients were included. Mean age was 32.7 years (range, 18-47 years). Mean follow-up was 21.9 months (range, 12-50 months). Mean number of injured structures was 11.9 (range, 10-16 structures) per patient. Physiotherapy duration had an effect on postoperative outcome in all six MHOQ domains (r = 0.821, p = 0.00001). However, no significant difference in overall hand function was found according to the number of injured structures (r = -0.105, p = 0.661). Precise initial evaluation, meticulous surgical treatment within 24 h and early physical therapy are essential after spaghetti-wrist injury. Good functional results are associated with prolonged physical therapy, but not with the number of structures injured.


The cation diffusion facilitator protein EmfA of Rhizobium etli belongs to a novel subfamily of Mn(2+)/Fe(2+) transporters conserved in α-proteobacteria.
Manganese (Mn(2+)) plays a key role in important cellular functions such as oxidative stress response and bacterial virulence. The mechanisms of Mn(2+) homeostasis are not fully understood, there are few data regarding the functional and taxonomic diversity of Mn(2+) exporters. Our recent phylogeny of the cation diffusion facilitator (CDF) family of transporters classified the bacterial Mn(2+)-CDF transporters characterized to date, Streptococcus pneumoniae MntE and Deinococcus radiodurans DR1236, into two monophyletic groups. DR1236 was shown to belong to the highly-diverse metal specificity clade VI, together with TtCzrB, a Zn(2+)/Cd(2+) transporter from Thermus thermophilus, the Fe(2+) transporter Sll1263 from Synechocystis sp and eight uncharacterized homologs whose potential Mn(2+)/Zn(2+)/Cd(2+)/Fe(2+) specificities could not be accurately inferred because only eleven proteins were grouped in this clade. A new phylogeny inferred from the alignment of 197 clade VI homologs revealed three novel subfamilies of uncharacterized proteins. Remarkably, one of them contained 91 uncharacterized α-proteobacteria transporters (46% of the protein data set) grouped into a single subfamily. The Mn(2+)/Fe(2+) specificity of this subfamily was proposed through the functional characterization of the Rhizobium etli RHE_CH03072 gene. This gene was upregulated by Mn(2+), Zn(2+), Cd(2+) and Fe(2+) but conferred only Mn(2+) resistance to R. etli. The expression of the RHE_CH03072 gene in an E. coli mntP/zitB/zntA mutant did not relieve either Zn(2+) or Mn(2+) stress but slightly increased its Fe(2+) resistance. These results indicate that the RHE_CH03072 gene, now designated as emfA, encodes for a bacterial Mn(2+)/Fe(2+) resistance CDF protein, having orthologs in more than 60 α-proteobacterial species.


Impact of individual and cumulative coronary risk factors on coronary flow reserve assessed by dobutamine stress echocardiography.
Traditional cardiovascular risk factors have been shown to cause microvascular dysfunction. Most studies that have evaluated microcirculation rely on invasive measurement tools. We used dobutamine stress echocardiography, a validated method to measure coronary flow velocity (CFV) and coronary flow reserve (CFR), in a previously unstudied population without known significant coronary artery disease to determine the impact of traditional risk factors on CFR. Consecutive patients who had no evidence of regional wall motion abnormalities at rest or during dobutamine stress echocardiography were studied. Left anterior descending artery CFV was measured at baseline and at peak dobutamine stress and CFR was calculated as the ratio of peak stress CFV to baseline CFV. Fifty-nine consecutive patients (28 men) with mean age of 66.8+/-14.5 years were studied. CFR was lower in patients with diabetes mellitus (DM) compared with those without (1.7+/-0.74 vs 2.48+/-0.98, p<0.007), in patients with hypertension compared with those without (2+/-0.8 vs 2.6+/-0.9, p<0.02), and in obese patients compared with nonobese patients (1.6+/-0.5 vs 2+/-0.6, p<0.02). CFR was further impaired in the presence of DM with hypertension, DM with obesity, DM with a wide pulse pressure (>50 mm Hg), and obesity with a wide pulse pressure. In a multivariate model, DM, obesity, and wide pulse pressure were significantly associated with variation in CFR (p<0.0008). In conclusion, CFR was abnormal in patients with DM, hypertension, and obesity. CFR impairment is exaggerated as the number of risk factors increases. Despite a negative dobutamine stress echocardiographic result, aggressive risk factor assessment and control should be implemented in patients with coronary risk factors due to an underlying abnormal CFR.


The Impact of Anticoagulation on COVID-19 (SARS CoV-2) Patient Outcomes: A Systematic Review.
Emerging data suggest that coagulopathy, cytokine storm, and acute respiratory distress syndrome are associated with the 2019 coronavirus disease (COVID-19). The prevalence of hypercoagulable state in these patients is unknown, but appears to be higher compared to those with other critically ill patients. Elevated D-dimer, large blood vessels clots, deep vein thrombosis, pulmonary embolism and disseminated intravascular coagulation have been reported in patients diagnosed with COVID-19 either on admission or during hospitalization and may be predictors of poor outcomes. We performed a comprehensive literature review using the search terms of COVID-19; severe acute respiratory syndrome coronavirus-2, coagulopathy, thrombosis and anticoagulation in PubMed, Ovid, google scholar, Medline and EMBASE databases from December 2019 to May 30, 2020. A total of 64 relevant studies were reviewed; of which, 4 studies met the inclusion criteria and were included for analysis. The majority of the studies were retrospective involving 525 critically ill COVID-19 patients. The most commonly studied anticoagulant administered was low molecular weight heparins. Anticoagulation dosing varied throughout the studies and may be classified as standard venous thromboembolism prophylaxis, intermediate dosing, or full dose anticoagulation. The most studied objective was improvement in coagulopathy. Significant reduction in D-dimer, improvement in coagulopathy markers such as Interlukin-6, fibrinogen degradation product level, as well as lymphocyte count were reported. Despite the limited quality of studies analyzed, prophylaxis and higher intensity dosed anticoagulation is associated with improved pulmonary oxygenation, decreased coagulopathy markers and decreased mortality in COVID-19 patients.


Serum zinc levels in celiac disease.
This study was done to determine the zinc levels in 30 children with celiac disease. Serum zinc level was estimated at inclusion and zinc supplementation was given for 3 months. Zinc levels were repeated at 3 and 6 months after inclusion. The serum zinc levels of newly diagnosed CD cases (0.64+/-0.34 microg/mL) versus controls (0.94+/-0.14 microg/mL) were significantly lower (95% CI -0.44 to -1.4), whereas in the old cases this difference was non-significant. The serum zinc level among severely malnourished and stunted celiac cases was also significantly lower irrespective of their treatment status. We conclude that serum zinc levels are low in newly diagnosed and severely malnourished children with celiac disease.


Relationships between gut microbiota, plasma metabolites, and metabolic syndrome traits in the METSIM cohort.
The gut microbiome is a complex and metabolically active community that directly influences host phenotypes. In this study, we profile gut microbiota using 16S rRNA gene sequencing in 531 well-phenotyped Finnish men from the Metabolic Syndrome In Men (METSIM) study. We investigate gut microbiota relationships with a variety of factors that have an impact on the development of metabolic and cardiovascular traits. We identify novel associations between gut microbiota and fasting serum levels of a number of metabolites, including fatty acids, amino acids, lipids, and glucose. In particular, we detect associations with fasting plasma trimethylamine N-oxide (TMAO) levels, a gut microbiota-dependent metabolite associated with coronary artery disease and stroke. We further investigate the gut microbiota composition and microbiota-metabolite relationships in subjects with different body mass index and individuals with normal or altered oral glucose tolerance. Finally, we perform microbiota co-occurrence network analysis, which shows that certain metabolites strongly correlate with microbial community structure and that some of these correlations are specific for the pre-diabetic state. Our study identifies novel relationships between the composition of the gut microbiota and circulating metabolites and provides a resource for future studies to understand host-gut microbiota relationships.


Changes in left ventricular anatomy and systemic hemodynamics induced by antihypertensive therapy with indenolol.
In 20 patients with mild or moderate essential hypertension who responded favorably to indenolol antihypertensive therapy, echocardiography was performed in the basal condition and 6 and 12 months after the beginning of permanent antihypertensive treatment. Indenolol induced a significant decrease in blood pressure, from a basal value of 170 +/- 3/100 +/- 8 mmHg to 142 +/- 4/87 +/- 2 mmHg after 6 months (p less than 0.01) and to 133 +/- 4/84 +/- 2 mmHg after 1 year (p less than 0.01), and in heart rate, from 72 +/- 5 to 61 +/- 3 bpm after 6 months (p less than 0.01) and to 60 +/- 2 bpm after 1 year (p less than 0.01). Simultaneously, there was a significant reduction in cardiac output (from 6.3 +/- .4 to 5.7 +/- .2 liters/min after 6 months, p less than 0.05, and to 5.6 +/- .2 liters/min after 1 year, p less than 0.01), due to a reduction in heart rate, increased stroke volume, and improved left ventricular performance after indenolol. Total peripheral resistance was also reduced, although statistical significance was not attained. However, a significant inverse correlation was found between the initial value of cardiac output and total peripheral resistance and the changes in these parameters induced by indenolol treatment (cardiac output: r = -0.824 and -0.855, total peripheral resistance: r = -0.876 and -0.899 at 6- and 12-month controls, respectively, all p less than 0.001). Finally, there was a parallel decrease in left ventricular wall and septal thickness and estimated left ventricular mass in patients with left ventricular hypertrophy, whereas no change in left ventricular anatomy could be detected in patients with normal left ventricular mass.


Pancreatitis of unusual origin.
The anatomic pattern seen in the three patients with contiguous gastric duplications associated with pancreatic ducts evidently predisposes the patient to pancreatitis. In the previous patient reported upon from this institution, the correlation of severe bleeding episodes with attacks of pancreatitis strongly supports the concept of blood blocking the pancreatic ductal system, thereby producing pancreatitis. Passage of viscous mucoid secretions from the aberrant gastric mucosa into the pancreatic ductal system also might retard the normal flow of pancreatic juice, producing elevation of the serum amylase level and pain. Overdistention of the gastric duplication also might be considered as a source of pain, but such mechanisms can be considered only speculation at present. Diagnosis is usually made after more than one exploratory laparotomy. Hemorrhage may result, should the gastric duplication contain parietal cells, leading to hemoductal pancreatitis, hematemesis or melena and anemia. At least one in five patients with a gastric duplication possesses another intestinal duplication. Developmental defects commonly are associated with gastric cysts. Almost identical anatomy was present in the patients with contiguous duplications. That two such rare pancreatic disorders were documented in the same institution within two years suggests that this pattern of developmental defect is more common that had previously been expected.


Collaborative e-learning using streaming video and asynchronous discussion boards to teach the cognitive foundation of medical interviewing: a case study.
Advances in electronic technology have created opportunities for new instructional designs of medical curricula. We created and evaluated a 4-week online elective course for medical students to teach the cognitive basis for interviewing skills. Ten students, from 2 medical schools, studied online modules on interviewing concepts and viewed videos illustrating the concepts. They then participated in asynchronous discussion groups designed to reinforce course concepts, stimulate reflective learning, and promote peer learning. In qualitative evaluations, learners reported improvements in self-awareness; increased understanding of interviewing concepts; and benefits of online learning vs face to face learning. Participants reported high levels of satisfaction with online learning and with achievement of course objectives. Self-reported knowledge scores increased significantly from pre-course completion to post-course completion. Online education has significant potential to augment curriculum on the medical interview, particularly among students trained in community settings geographically distant from their academic medical center.


The use of large language models in medicine: proceeding with caution.
Large language models, like ChatGPT and Bard, have potential clinical applications due to their ability to generate conversational responses and encode medical knowledge. However, their clinical adoption faces challenges including hallucinations, lack of transparency, and lack of consistency. Ethicolegal concerns surrounding patient consent, legal liability, and data privacy further complicate matters. Despite their promise, an optimistic but cautious approach is essential for the safe integration of large language models into clinical settings.


Enucleation vs Ophthalmic Artery Chemosurgery for Advanced Intraocular Retinoblastoma: A Retrospective Analysis.
Ophthalmic artery chemosurgery (OAC) has emerged as a primary treatment for advanced-stage retinoblastoma. To our knowledge, the incidence of orbital recurrence in eyes treated with OAC has not been described. To determine the incidence of orbital recurrence following enucleation or OAC as primary treatments for advanced-stage retinoblastoma. Single-institution cohort study with retrospective record review at an academic ophthalmic oncology practice. A total of 140 eyes in 135 patients who presented between February 14, 2006, and March 4, 2014, and were classified as having Reese-Ellsworth group 5 or International Classification of Retinoblastoma (Children's Oncology Group) group D or E retinoblastoma were included; 63 patients (63 eyes) were primarily treated with enucleation and 72 patients (77 eyes) were primarily treated with OAC. This analysis was conducted between August 1, 2014, and March 1, 2015. Incidence of and time to orbital recurrence, metastasis, and death. There were 5 orbital recurrences (incidence, 7.9%) in the primary enucleation group and 1 orbital recurrence (incidence, 1.3%) in the primary OAC group during median follow-up times of 42.6 months (range, 6.2-97.1 months) and 38.7 months (range, 9.0-104.3 months), respectively. The 24-month Kaplan-Meier estimate for orbital recurrence-free survival was worse for the enucleation group (92.1%; 95% CI, 82.0-96.7) than for the OAC group (100%) (log-rank test, P = .049). The enucleation group had 5 cases of metastatic disease (7.9%) and 2 deaths (3.2%). In the OAC group, there were 3 cases of metastatic disease (4.2%) and no deaths. Kaplan-Meier analysis of metastasis-free survival and overall survival yielded no differences between the 2 treatment groups. Analysis of a number of features of the 2 groups revealed more eyes with iris neovascularization in the enucleation group (25.4%) than in the OAC group (5.2%) and more eyes with group E retinoblastoma in the enucleation group (87.3%) than in the OAC group (29.9%), although neither of these factors was an independent predictor of orbital relapse in a Cox proportional hazards model. In this single-institution retrospective study of advanced intraocular retinoblastoma, there were more orbital recurrences in the group primarily treated with enucleation. Ophthalmic artery chemosurgery for advanced intraocular retinoblastoma was not found to increase the chance of orbital recurrence, metastatic disease, or death compared with primary enucleation.


Recommendations to institutions.
Results from the Interdisciplinary Generalist Curriculum (IGC) Project support current ideas of management within a chaotic environment. Important aspects of building support for educational innovation included the following. The trend toward primary care and request for proposal process were important catalysts for change. Buy-in from the dean and key opinion leaders was essential. Early identification of champions for the proposal and ability to achieve broad consensus helped shape coherent projects. Being able to read the culture of the institution and accede to pragmatic changes were important for bridging the initial implementation and maintenance of the change. IGC Project leaders were quick to identify key leverage points, both internal and external. The recommendations of key school committees and licensing bodies were used to foster ongoing change. A respected home for the project on neutral ground was sought. Dedicated coordinators helped sustain daily details, while developing rewards and recognition for collaboration supported faculty involvement. New relationships fostered new systems, which the projects used to continue after funding lapsed and to successfully apply for other grants and contracts.


Optical Coherence Tomography in Cardiac Allograft Vasculopathy: State-of-the-Art Review.
Cardiac allograft vasculopathy (CAV) is a challenging complication of heart transplantation. CAV pathophysiology is incompletely understood, standard screening modalities such as angiography have significant limitations, and currently available therapies have only modest efficacy in preventing progression. Optical coherence tomography is a light-based technique that provides microscopic level catheter-based intravascular imaging and has dramatically expanded our understanding of CAV, demonstrating it to be a complex, heterogeneous, and dynamic process. This review covers characteristics and uses of optical coherence tomography, including vessel characterization, serial use to assess progression of disease, guiding percutaneous intervention, and monitoring response to CAV therapies. We also discuss the potential of optical coherence tomography in providing individualized assessment and enable customized CAV therapies, which may lead to improvements in long-term transplant outcomes.


[Induction of dietetic diabetes in Microtus arvalis Pallas and its developmental mechanism].
In Microtus arvalis Pallas, new born voles were fostered to ICR mice and supplied with pellets for mice after weaning. A high concentration of glycosuria was shown in about 50% of the voles and continued for over ten weeks. Concentrations of blood glucose and plasma FFA iun glycosuric voles were three or four times as high as those in normal controls. The fermentation ability and pH lowered in the esophageal sac, and comparatively large amount of starch existed in the pyloric stomach of the glycosuric voles. This demonstrated that the dietary starch were tolerably transported to the pyloric stomach without being fermented in the esophageal sac. Glycosuria was also induced in about 50% of the voles supplied with an acidified water (0.02 N HCl, pH 1.7), and the glycosuric voles showed a low pH (1.4-4.2) and lowering of the fermentative ability in esophageal sac. Such an abnormal fermented conditions in the esophageal sac is considered to induce glycosuria in the voles. Glucose tolerance in the diabetic voles which were supplied with pellets for mice lowered considerably with the progress of the disease. On the other hand, plasma insulin levels in the slight diabetic cases rose to eight times as high as normal level, but they lowered considerably with the progress. In the serious cases, the voles fell into complete insulin deficiency. From the above results, the herbivorous Microtus species was considered to be useful as an "animal model" of the dietetic diabetes.


Violent phenotype in SAL mice is inflexible and fixed in adulthood.
Violence was shown to be qualitatively different from functional hyper-aggression in mice selected for high aggression namely Short Attack Latency (SAL), Turku Aggressive (TA) and North Carolina (NC900) strains. This study aimed at investigating whether this adulthood violent phenotype as seen previously in the SAL mice is fixed and hence behaviorally inflexible right from day 1 of the experiment or consequential, i.e., subject to gradual change from functional aggression to violence. The functionally hyper-aggressive strains namely TA and NC900 strains served as controls for the study. Methodologically, behavioral (in)flexibility was studied using the overall sequential structure of agonistic behavior. In particular, intra-individual variations in the overall agonistic behavior as well as offensive, pre- and post-offensive behavior transitions, directly related to the resident-intruder interactions were investigated. The SAL mice showed the least intra-individual variation in their overall sequential agonistic structure as well as a fixed offense-oriented agonistic behavior of highest magnitude when compared with the other strains. Additionally, the pre- and post- offensive transitions were most salient in the functionally hyper-aggressive TA and NC900 strains, whereas virtually absent in the SAL mice. Thus, the violent behavior of the adult SAL mice is behaviorally inflexible or fixed, whereas the functionally hyper-aggressive behavior of the adult TA and NC900 mice is behaviorally flexible and constantly adaptive to the opponent behavior, over 3 days of repeated resident-intruder interaction.


Improved Stability and Targeted Cytotoxicity of Epigallocatechin-3-Gallate Palmitate for Anticancer Therapy.
Although with high antioxidant activity, epigallocatechin-3-gallate (EGCG) was restricted by its poor chemical stability in practical applications. One of EGCG derivatives, EGCG palmitate, was synthesized with EGCG and palmitoyl chloride to overcome instability of EGCG. However, uncertainties still exist in chemical stability and cytotoxicity of EGCG palmitate, which are essential for further exploration in anticancer therapy. Our work aims to analyze the resistance of EGCG palmitate to oxidation and summarize its targeted inhibition efficiency on cancerous cells and normal cells. High-performance liquid chromatography analysis confirmed that EGCG palmitate remained stable in air and Dulbecco's modified eagle medium (DMEM) for a longer time than EGCG. Antioxidative and pro-oxidative effects of EGCG palmitate on treated cells are proposed through reactive oxygen species (ROS) detection, respectively. It reveals that pro-oxidants by H2O2 production can exert antiproliferative and proapoptotic effects on cancerous cells and stimulate autophagy, while an antioxidant relieves oxidative stress caused by superoxide as compared to normal cells. Consequently, targeted cytotoxicity is adopted by EGCG palmitate-treated cancerous cells. Results above manifest that EGCG palmitate possesses potential to serve as a promising prodrug in anticancer treatment.


Observations of the andromeda galaxy at 11-centimeter wavelength.
Observations of the Andromeda galaxy (M31) at 2695 megahertz reveal more detail than do earlier measurements at lower frequency. The region is highly confused but there is apparently a more dense clustering of sources within the optical outline of the galaxy than without. One source (OA33) near M31 has an interesting. flat spectrum.


Erratic charge transfer dynamics of Au/ZnTiO3 nanocomposites under UV and visible light irradiation and their related photocatalytic activities.
The present article presents an in-depth discussion on the state-of-the-art multifarious roles of Au nanoparticles and their associated charge anti-recombination process in burgeoning photocatalysis research. Hexagonal-phase ZnTiO3 was fabricated through a sol-gel auto-combustion method by optimizing the calcination temperatures. To further improve the charge separation efficiency and visible light induced photocatalytic activity of pristine ZnTiO3, we designed a new type of Au/ZnTiO3 nanocomposite by a precipitation-deposition method. The photocatalytic activities of the Au/ZnTiO3 nanocomposites were substantiated by evaluating the rate of hydrogen evolution under both UV and visible light illumination. The photocatalytic activity of the Au/ZnTiO3 nanocomposites rises proportionally with an increase in Au content up to 1.5 wt% under UV light illumination and it produce around 285 μmol h-1 of H2 which is approximately 2.6 times higher than that produced by pristine ZnTiO3. Therefore, the Au nanoparticles present on the surface of ZnTiO3 act as electron acceptors, leading to an increase in the rate of generation and separation of charge carriers. This process helps to enhance the congregation of electrons on Au nanoparticles through the Schottky junction. The obtained results are very consistent with steady-state PL and UV light induced photocurrent measurements. Conversely, such a trend was not detected under visible light illumination. The visible light induced photocatalytic activity of Au/ZnTiO3 nanocomposites increases with a rise in Au content up to 1 wt% and thereafter decreases with further Au loading. Therefore, the initial increment in photocatalytic activity is due to the generation, separation and participation of a large number of SPR-induced charge carriers and thereafter decreases due to the recombination of SPR-generated charge carriers because of the formation of defect sites at the Au and ZnTiO3 interface. That the excess Au loading causes the recombination of SPR charge carriers was well explained by undertaking SPR-induced TRPL analysis and this result is directly followed up with the results of visible light induced photocurrent and EIS measurements. The Au/ZnTiO3 nanocomposites with optimal Au loading (1 wt%) delivered an amazingly high rate of hydrogen evolution i.e. 108 μmol h-1 with an energy conversion efficiency of 7.14%, whereas pristine ZnTiO3 shows negligible activity under visible light illumination.


Molecular dynamics lattice gas equilibrium distribution function for Lennard-Jones particles.
The molecular dynamics lattice gas (MDLG) method maps a molecular dynamics (MD) simulation onto a lattice gas using a coarse-graining procedure. This is a novel fundamental approach to derive the lattice Boltzmann method (LBM) by taking a Boltzmann average over the MDLG. A key property of the LBM is the equilibrium distribution function, which was originally derived by assuming that the particle displacements in the MD simulation are Boltzmann distributed. However, we recently discovered that a single Gaussian distribution function is not sufficient to describe the particle displacements in a broad transition regime between free particles and particles undergoing many collisions in one time step. In a recent publication, we proposed a Poisson weighted sum of Gaussians which shows better agreement with the MD data. We derive a lattice Boltzmann equilibrium distribution function from the Poisson weighted sum of Gaussians model and compare it to a measured equilibrium distribution function from MD data and to an analytical approximation of the equilibrium distribution function from a single Gaussian probability distribution function. This article is part of the theme issue 'Progress in mesoscale methods for fluid dynamics simulation'.


Large-cell acanthoma of the eyelid. Report of two cases.
We describe two cases of large-cell acanthoma that involved the skin of the upper eyelid. Patient 1 was a 71-year-old white man with a pale, well-demarcated papillomatous plaque of 3 months' duration. Patient 2 was a 62-year-old white man with a sharply demarcated plaque-like thickening of the pretarsal skin involving the eyelid margin of 2 years' duration. In both cases, the histopathologic findings were similar and showed an abrupt transition at the edge of the lesion between the normal epidermis and the acanthotic plaque, which displayed hyperkeratosis, hypergranulosis, and focal parakeratosis. The localized epidermal thickening showed enlarged keratocytes that appeared twice their normal size. To our knowledge, this is the first report of large-cell acanthoma involving the eyelid.


An enthalpy landscape view of homogeneous melting in crystals.
A detailed analysis of homogeneous melting in crystalline materials modeled by empirical interatomic potentials is presented using the theory of inherent structures. We show that the homogeneous melting of a perfect, infinite crystalline material can be inferred directly from the growth exponent of the inherent structure density-of-states distribution expressed as a function of formation enthalpy. Interestingly, this growth is already established by the presence of very few homogeneously nucleated point defects in the form of Frenkel pairs. This finding supports the notion that homogeneous melting is appropriately defined in terms of a one-phase theory and does not require detailed consideration of the liquid phase. We then apply this framework to the study of applied hydrostatic compression on homogeneous melting and show that the inherent structure analysis used here is able to capture the correct pressure-dependence for two crystalline materials, namely silicon and aluminum. The coupling between the melting temperature and applied pressure arises through the distribution of formation volumes for the various inherent structures.


Complications and Mortality Following One to Two-Level Anterior Cervical Fusion for Cervical Spondylosis in Patients Above 80 Years of Age.
A retrospective database review. The aim of this study was to determine the complication and mortality rates in patients 80 years of age and older who were treated with anterior cervical fusion surgery and to compare these rates against those of other elderly patients. Cervical spondylosis is frequently observed in the elderly and is the most common cause of myelopathy in older adults. With increasing life expectancies, a greater proportion of patients are being treated with spine surgery at a later age. Limited information is available regarding outcomes following anterior cervical fusion surgery in patients 80 years of age or older. Medicare data from the PearlDiver Database (2005-2012) were queried for patients who underwent primary one to two-level anterior cervical spine fusion surgeries for cervical spondylosis. After excluding patients with prior spine metastasis, bone cancer, spine trauma, or spine infection, this cohort was divided into two study groups: patients 65 to 79 (51,808) and ≥80 years old (5515) were selected. A cohort of matched control patients was selected from the 65 to 79-year-old and 90-day complication rates and 90-day and 1-year mortality rates were compared between cohorts. The proportion of patients experiencing at least one major medical complication was relatively increased by 53.4% in patients aged ≥80 years [odds ratio (OR) 1.63]. Patients 80 years of age or older were more likely to experience dysphagia (OR 2.16), reintubation (OR 2.34), and aspiration pneumonitis (OR 3.17). Both 90-day (OR: 4.34) and 1-year (OR 3.68) mortality were significantly higher in the ≥80 year cohort. Patients 80 years of age or older are more likely to experience a major medical complication or mortality following anterior cervical fusion for cervical spondylosis than patients 65 to 79 years old. Dysphagia, aspiration pneumonitis, and reintubation rates are also significantly higher in patients 80 years of age or older. Although complication rates may be higher in this patient population, carefully selected patients could potentially derive much benefit from surgery and should not be screened out solely on the basis of age. 4.


Development of in vitro-in vivo correlation of parenteral naltrexone loaded polymeric microspheres.
Establishment of in vitro-in vivo correlations (IVIVCs) for parenteral polymeric microspheres has been very challenging, due to their complex multiphase release characteristics (which is affected by the nature of the drug) as well as the lack of compendial in vitro release testing methods. Previously, a Level A correlation has been established and validated for polymeric microspheres containing risperidone (a practically water insoluble small molecule drug). The objectives of the present study were: 1) to investigate whether a Level A IVIVC can be established for polymeric microspheres containing another small molecule drug with different solubility profiles compared to risperidone; and 2) to determine whether release characteristic differences (bi-phasic vs tri-phasic) between microspheres can affect the development and predictability of IVIVCs. Naltrexone was chosen as the model drug. Three compositionally equivalent formulations of naltrexone microspheres with different release characteristics were prepared using different manufacturing processes. The critical physicochemical properties (such as drug loading, particle size, porosity, and morphology) as well as the in vitro release characteristics of the prepared naltrexone microspheres and the reference-listed drug (Vivitrol®) were determined. The pharmacokinetics of the naltrexone microspheres were investigated using a rabbit model. The obtained pharmacokinetic profiles were deconvoluted using the Loo-Riegelman method, and compared with the in vitro release profiles of the naltrexone microspheres obtained using USP apparatus 4. Level A IVIVCs were established and validated for predictability. The results demonstrated that the developed USP 4 method was capable of detecting manufacturing process related performance changes, and most importantly, predicting the in vivo performance of naltrexone microspheres in the investigated animal model. A critical difference between naltrexone and risperidone loaded microspheres is their respective bi-phasic and tri-phasic release profiles with varying burst release and lag phase. These variations in release profiles affect the development of IVIVCs. Nevertheless, IVIVCs have been established and validated for polymeric microspheres with different release characteristics.


Fetal injury with midtrimester diagnostic amniocentesis.
One hundred seven infants born after midtrimester amniocentesis were examined. The frequency of fetal injury was 9%, and was directly related to the number of attempts at amniocentesis. All were minor cutaneous injuries except for 1 case of disruption of a patellar tendon. Suggestions are made regarding ways to reduce the incidence of fetal puncture.


Safety of pressure-volume curve measurement in acute lung injury and ARDS using a syringe technique.
To assess the safety of frequent pressure-volume (PV) curve measurement in patients with acute lung injury (ALI)/ARDS. Prospective observational study. Academic medical-surgical critical care unit. Consecutive patients with ALI or ARDS. Static inspiratory PV curves of the respiratory system were determined twice on day 1, then once daily for up to 6 days using a syringe. At each time point, three separate measurements of the PV curve were made. A 100-mL graduated syringe was used to inflate patients' lungs with 50- to 100-mL increments up to an airway pressure of 45 cm H(2)O or a total volume of 2 L; each volume step was maintained for 2 to 3 s until a plateau airway pressure was recorded. Outcome measures were mean arterial BP, heart rate (HR), and oxyhemoglobin saturation (SpO(2)) prior to and immediately after PV curve measurement. There were a priori criteria for procedure discontinuation if poorly tolerated. Eleven patients were enrolled with a total of 134 PV curves generated. SpO(2) was 93 +/- 4% (mean +/- SD) before and fell to a nadir of 89 +/- 5% during PV curve measurement (p < 0.001), but increased to 97 +/- 4% immediately afterwards (p < 0.001, before vs after). HR rose from 106 +/- 22 to 108 +/- 22 beats/min immediately after the maneuver (p < 0.001). Mean arterial BP was 93 +/- 15 mm Hg before and 100 +/- 17 mm Hg immediately afterwards (p < 0.001). During PV curve measurement, systolic BP in one patient fell to 64 mm Hg from 113 mm Hg; in another patient, SpO(2) dropped to 79% from 89%. Both changes were transient. The study was discontinued in one patient because of inability to tolerate zero positive end-expiratory pressure; in another patient, the study was discontinued because of the development of subcutaneous emphysema. PV curve measurement by syringe technique is well tolerated in most patients. Nonetheless, the maneuver may cause significant changes in oxygenation and/or hemodynamics, necessitating close monitoring.


Nanomaterials in the construction industry: a review of their applications and environmental health and safety considerations.
The extraordinary chemical and physical properties of materials at the nanometer scale enable novel applications ranging from structural strength enhancement and energy conservation to antimicrobial properties and self-cleaning surfaces. Consequently, manufactured nanomaterials (MNMs) and nanocomposites are being considered for various uses in the construction and related infrastructure industries. To achieve environmentally responsible nanotechnology in construction, it is important to consider the lifecycle impacts of MNMs on the health of construction workers and dwellers, as well as unintended environmental effects at all stages of manufacturing, construction, use, demolition, and disposal. Here, we review state-of-the-art applications of MNMs that improve conventional construction materials, suggest likely environmental release scenarios, and summarize potential adverse biological and toxicological effects and their mitigation. Aligned with multidisciplinary assessment of the environmental implications of emerging technologies, this review seeks to promote awareness of potential benefits of MNMs in construction and stimulate the development of guidelines to regulate their use and disposal to mitigate potential adverse effects on human and environmental health.


Racial Disparities in Diabetes Management Outcomes: Evidence from a Remote Patient Monitoring Program for Type 2 Diabetic Patients.
Introduction: Despite growing documentation of the efficacy of telemedicine in diabetes management, racial disparities in telemedicine-facilitated diabetes management remain underexplored. This study examined disparities in diabetes management outcomes between black and white patients with type 2 diabetes (T2D) in a remote monitoring program. Methods: The analysis sample included 914 white T2D patients and 365 black T2D patients in Nebraska who completed a 3-month remote patient monitoring and coaching after hospital discharge from 2014 to 2017. Ordinary least squares regression was estimated to examine racial differences in hemoglobin A1c (HbA1c), and logistic regression was used to determine the odds of HbA1c > 9% at the end of the program, controlling for demographics, baseline health conditions, and patient activation and engagement with the program. Results: The proportion of white patients with HbA1c > 9% was reduced from 16% at the baseline to 7% at program completion, and the corresponding reduction among black patients was from 30% to 18%. After adjusting for the effects of baseline HbA1c and other covariates, the average HbA1c among black patients at the end of the program was 0.23 points higher than that among white patients (p < 0.01), and the adjusted odds of black patients having HbA1c > 9% was 1.68 times that of white patients (95% confidence interval [1.07-2.63]). Discussion: The remote patient monitoring and coaching program reduced the absolute gap between black and white T2D patients. However, substantial racial disparities in HbA1c still remained at the end of the program and warranted further research.


Stability of a gold nanoparticle-DNA system in seawater.
We investigated the stability of gold nanoparticles (AuNPs) in seawater. The large amount of Na+, Mg2+, K+, and Ca2+ in seawater makes AuNPs unstable resulting in immediate aggregation. We found that AuNPs become much more stable when they were treated with polyethylene glycol (PEG, MW = 20, 000) before exposure to seawater. The AuNPs maintained stability up to 10 days when they were treated with 16.6% PEG 20000. The AuNP-DNA complex formed in the presence of 3.3% PEG 20000 maintained stability when exposed to seawater. We also demonstrated that the AuNP-DNA complexes can be redispersed after centrifugation and show sequence-specific aggregation in seawater. The results show that the both AuNPs and an AuNP-DNA system can be used in seawater and have the potential to be used to study marine systems.


Serum betaine is inversely associated with low lean mass mainly in men in a Chinese middle-aged and elderly community-dwelling population.
Previous studies have demonstrated that betaine supplements increase lean body mass in livestock and improve muscle performance in human beings, but evidence for its effect on human lean mass is limited. Our study assessed the association of circulating betaine with lean mass and its composition in Chinese adults. A community-based study was conducted on 1996 Guangzhou residents (weight/mass: 1381/615) aged 50-75 years between 2008 and 2010. An interviewer-administered questionnaire was used to collect general baseline information. Fasting serum betaine was assessed using HPLC-MS. A total of 1590 participants completed the body composition analysis performed using dual-energy X-ray absorptiometry during a mean of 3·2 years of follow-up. After adjustment for age, regression analyses demonstrated a positive association of serum betaine with percentage of lean mass (LM%) of the entire body, trunk and limbs in men (all P<0·05) and LM% of the trunk in women (P=0·016). Each sd increase in serum betaine was associated with increases in LM% of 0·609 (whole body), 0·811 (trunk), 0·422 (limbs), 0·632 (arms) and 0·346 (legs) in men and 0·350 (trunk) in women. Multiple logistic regression analysis revealed that the prevalence of lower LM% decreased by 17 % (whole body) and 14 % (trunk) in women and 23 % (whole body), 28 % (trunk), 22 % (arms) and 26 % (percentage skeletal muscle index) in men with each sd increment in serum betaine. Elevated circulating betaine was associated with a higher LM% and lower prevalence of lower LM% in middle-aged and elderly Chinese adults, particularly men.


Ultrastructural immunostaining of infiltrating ductal breast carcinomas with the monoclonal antibody H: a comparative study with cytokeratin 8.
The monoclonal antibody H (mAbH) detects an epitope consisting of an O-linked N-acetyl glucosamine (O-GlcNAc) and neighboring amino acids. This epitope has been found by using extracts from the MCF-7 human breast carcinoma cell line in immunoblotting experiments, on cytokeratin 8 (CK8) and 5 other polypeptides. In the present study, a double immunogold method was applied for the colocalization of CK8 and mAbH epitope on epoxy thin sections in 18 cases of infiltrating ductal breast carcinomas (IDBC) and in 6 cases of fibroadenomas, to study the accurate subcellular distribution of CK8 in breast cancer cells, as compared to the 5 polypeptides, recognized by mAbH. Furthermore, a detailed quantitative evaluation of the double immunolocalization over the cellular compartments of cancer cells was undertaken with the aid of a computerized image analysis system and the results were assessed statistically. The distribution pattern of CK8 and the mAbH epitope in the neoplastic mammary epithelial cells was similar in IDBC as compared to fibroadenomas, while the gold labeling intensity of these epitopes differed over the cellular compartments between malignant and benign biopsies. The results reveal the significance of the role of CK8 and O-GlcNAc glycosylation in the biology of the neoplastic mammary cells in vivo, determining their malignant potential.


Consumers' sensory and nutritional perceptions of three types of milk.
To identify consumer perceptions of whole milk, reduced-fat milk and soy milk, and to investigate demographic influences on perceptions and types of milk consumption. Questionnaires covering nutritional and sensory perceptions of three types of milk. Three hundred and sixty-one randomly selected shoppers in Melbourne, Australia. Generally, respondents held positive perceptions about milk. Milk was considered as having good sensory properties, providing a good source of nutrients, and being a convenient and safe product. However, despite these findings, misperceptions and unawareness about the nutrient content of milk were prevalent. Negative perceptions were most common for whole milk and were mostly related to its perceived high fat, cholesterol and energy contents. Soy milk received lower ratings on sensory quality and convenience than dairy milk. There were few sociodemographic differences in consumers' perceptions. Although reduced-fat milk consumption was more frequent among elderly people and type of milk consumption was related to parenthood, no other significant effects of demographic variables were found on the consumption of specific milk types. Although positive perceptions were common, negative perceptions and misperceptions appear to be prevalent, presenting a challenge for nutrition education. Sociodemographic factors were not shown to be important predictors of perceptions and type of milk consumption.


Centrosomal Protein CEP135 Regulates the Migration and Angiogenesis of Endothelial Cells in a Microtubule-Dependent Manner.
Angiogenesis is the formation of blood vessels by sprouting from mature blood vessels and is regulated by multiple factors; however, the role of centrosome and centrosomal proteins (CEP) in angiogenesis needs further study. centrosomal protein 135 (CEP135) is an important centrosome-associated protein that can affect a variety of cellular processes, such as the cell cycle, but its effect on angiogenesis is still unknown. Tube formation and in vivo angiogenesis assays were performed to confirm the effects of CEP135 on endothelial cell (EC) angiogenesis in vitro and in mice. Cell counting kit-8 (CCK-8), 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry (FCM) and immunoblot assays were performed to confirm the effects of CEP135 on the proliferation and cell cycle of endothelial cells. Wound healing, transwell, and fluorescence staining were performed to confirm its effects on EC cell migration, polarization, and spindle orientation, and a tubulin turbidity assay was performed to confirm its effects on microtubule stabilization. We conducted a series of experiments to explore the potential role of CEP135 in angiogenesis. CEP135 siRNA obviously inhibits angiogenesis in vivo compared with the control. CEP135 could mediate cell proliferation and the cell cycle by mediating spindle orientation. Moreover, we showed that CEP135 is involved in the regulation of angiogenesis by affecting the migration of endothelial cells using wound closure and transwell assays. We further demonstrated that CEP135 promotes endothelial polarization and microtubule stability, thus affecting cell migration. CEP135 was involved in the polarization of centrosomes, which is important for the migration of human umbilical vein ECs (HUVECs). These findings indicated that CEP135 may promote the polarization of HUVECs and accelerate migration, which in turn promotes angiogenesis.


Racial and ethnic differences in asthma diagnosis among children who wheeze.
Racial and ethnic disparities exist in reported childhood asthma prevalence, but it is unclear if disparities stem from true prevalence differences or a different likelihood of receiving a diagnosis from a health professional. Concern has been raised that asthma may be underdiagnosed, particularly among minority children who have more restricted access to high-quality health care. To examine racial/ethnic differences among currently symptomatic children in acquiring an asthma diagnosis to determine if relative underdiagnosis among minorities exists. Children for whom no symptoms were reported (a group that includes those with well-controlled symptoms) were excluded from the analysis. The 1999 National Health Interview Survey includes a nationally representative sample of children with reported wheezing symptoms. We included children 3 to 17 years old in the study and analyzed racial/ethnic differences in asthma diagnosis, controlling for young age, gender, parental education, single-parent household, central-city residence, region of residence, health insurance, having a usual place of care, and parent-reported severity of wheezing symptoms. Among those reported to have wheezed in the past year (n = 946), 83% of Puerto Rican, 71% of non-Hispanic black, and 65% of Mexican children were diagnosed with asthma compared with 57% of non-Hispanic white children. Using non-Hispanic white children as the reference group, the approximate adjusted relative risk for physician diagnosis of asthma given wheezing in the past year was 1.43 (95% confidence interval [CI]: 1.04, 1.63) for Puerto Rican, 1.22 (95% CI: 1.03, 1.37) for non-Hispanic black, and 1.19 (95% CI: 0.94, 1.39) for Mexican children. Minority children were reported to have greater severity of wheezing symptoms. Even after accounting for this increased severity, children in racial and ethnic minority groups were as or more likely to have a reported asthma diagnosis than non-Hispanic white children. Our findings do not provide evidence for the hypothesis that symptomatic minority children are underdiagnosed with asthma compared with non-Hispanic white children. To the contrary, among currently symptomatic children, minority children were more likely to be diagnosed than non-Hispanic white children even after accounting for the higher wheezing severity among minority children.


Clinical utility of echocardiography in the management of implantable ventricular assist devices.
The high mortality rate of congestive cardiac failure, the cost and complications of cardiac transplantation, and the waiting list mortality rate resulting from donor organ scarcity have encouraged the development of surgical techniques as bridges to transplantation or as long-term palliative therapy. Implantable left ventricular assist devices are now routinely used as such a bridge, and within the REMATCH Trial, as permanent palliative devices in nontransplant candidates. These are mechanical managements with myriad mechanical complications and pitfalls. Echocardiography has been extensively used in our institution to detect and diagnose previously documented and hitherto unencountered complications of these procedures. The role of echocardiography in these procedures, including preoperative patient selection, intraoperative transesophageal echocardiography, and postoperative troubleshooting and late follow-up, is discussed. We describe our clinical echocardiographic approach, which has developed over 91 assist-device procedures. The relative frequency and clinical impact of specific anatomic, physiologic, hemodynamic, and mechanical features are described. New techniques such as the Doppler quantification of assist device inflow obstruction are illustrated, as are the device cannula position, the detection of device valve failure, and the parameters related to the remodeling procedure. Echocardiography in heart failure surgery has proved to be an invaluable tool in the diagnosis and management of mechanical complications. The experience gained in our institution may serve as an aid to new surgical programs treating these critically ill patients.


Atomic-Level Microstructure of Efficient Formamidinium-Based Perovskite Solar Cells Stabilized by 5-Ammonium Valeric Acid Iodide Revealed by Multinuclear and Two-Dimensional Solid-State NMR.
Chemical doping of inorganic-organic hybrid perovskites is an effective way of improving the performance and operational stability of perovskite solar cells (PSCs). Here we use 5-ammonium valeric acid iodide (AVAI) to chemically stabilize the structure of α-FAPbI3. Using solid-state MAS NMR, we demonstrate the atomic-level interaction between the molecular modulator and the perovskite lattice and propose a structural model of the stabilized three-dimensional structure, further aided by density functional theory (DFT) calculations. We find that one-step deposition of the perovskite in the presence of AVAI produces highly crystalline films with large, micrometer-sized grains and enhanced charge-carrier lifetimes, as probed by transient absorption spectroscopy. As a result, we achieve greatly enhanced solar cell performance for the optimized AVA-based devices with a maximum power conversion efficiency (PCE) of 18.94%. The devices retain 90% of the initial efficiency after 300 h under continuous white light illumination and maximum-power point-tracking measurement.


Direct determination of the lamellar structure of peripheral nerve myelin at moderate resolution (7A).
Low-angle X-ray diffraction patterns have been recorded from normal nerve and nerve swollen in glycerol solutions. The new X-ray data have a resolution of 7 A. Direct methods of structure analysis which include deconvolution of the auto-correlation function and sampling theorem reconstructions have been used in the interpretation of the X-ray data. Phases have been assigned to the first 12 orders of diffraction from normal nerve. Fourier syntheses at a resolution of 7 A are described and an absolute electron density scale is derived. A possible molecular interpretation of the electron density profile is given.


Chemoproteomic Profiling of 8-Oxoguanosine-Sensitive RNA-Protein Interactions.
Cellular nucleic acids are subject to assault by endogenous and exogenous agents that can perturb the flow of genetic information. Oxidative stress leads to the accumulation of 8-oxoguanine (8OG) in DNA and RNA. 8OG lesions on mRNA negatively impact translation, but their effect on global RNA-protein interactions is largely unknown. Here, we apply an RNA chemical proteomics approach to investigate the effect of 8OG on RNA-protein binding. We find proteins that bind preferentially to 8OG-modified RNA, including IGF2BP1-3 and hnRNPD, and proteins that are repelled by 8OG such as RBM4. We characterize these interactions using biochemical and biophysical assays to quantify the effect of 8OG on binding and show that a single 8OG abolishes the binding of RBM4 to its preferred CGG-containing substrate. Taken together, our work establishes the molecular consequences of 8OG on cellular RNA-protein binding and provides a framework for interrogating the role of RNA oxidation in biological systems.


Mechanisms in the Competitive Success of an Invading Sexual Gecko over an Asexual Native.
The competitive displacement by a sexual gecko species of an asexual resident gecko has been documented over a wide geographic area. To test hypotheses concerning the detailed mechanism of this displacement, an experimental system was developed to follow populations of geckos in a duplicated, controlled environment that closely approximates the natural arena for the competitive interaction. Asymmetric competition occurred only in the presence of light, which attracts a dense concentration of insect food sources. The mechanism of competition was partly due to the behavioral dominance of the larger sexual species over the smaller asexual species in areas near the concentrated food. However, this behavior resulted from an avoidance response of subordinate asexuals rather than overt aggression by the sexual species.